Incomplete suppression of HIV replication and consequent development of resistance continue to mar AIDS therapy. The underlying problems include efficacy, non-adherence and infected cell reservoirs. Although new drugs targeting entry, integration or transcription will ameliorate some problems, achieving a more complete solution necessitates turning to novel and compementary therapies. Among several, effective gene therapy approaches available for HIV-1 are RNA aptamers targeted to HIV-1. Aptamers are known for their specificity, high affinity, stability and the absence of immunogenicity. Recent work has provided convincing evidence that intracellular aptamers targeted to HIV-1 can strongly suppress viral replication. Mutations conferring resistance to such aptamers have led to loss of viral fitness. Thus, there is a hitherto un-utilized opportunity to develop anti-HIV agents of unique specificity (reducing toxicity), that would more completely suppress HIV-1 replication, hinder or slow-down resistance and eliminate non-adherence. To this end, the following collaborative research program involving the respective organizations/investigators is proposed. 1. Accacia LLC, Int (Austin, TX) in partnership with Andy Ellington (University of Texas, Austin), will perform high throughput selection of RNA aptamers to HIV-1 targets, identify tight-binders, determine and further optimize in vitro efficacies. 2. Vinayaka Prasad (AECOM) will use pre-selected aptamers from Accacia to determine efficacy of inhibition of HIV/SHIV replication, determine mechanism of inhibition and select for aptamer-resistance. He will provide Accacia with resistant proteins for developing second generation aptamers. 3. Paul Johnson (NEPRC) will introduce the best aptamers, via retroviral vectors, into macaque CD34+ve cells, transplant them into macaques, examine levels of gene marking in uninfected macaques, as well as test the efficacy of the aptamers to protect CD4 +ve T cells derived from marked CD34 +ve cells in vivo.